Pharmacokinetics and Safety of Remdesivir in Pregnant and Nonpregnant Women With COVID-19: Results From IMPAACT 2032-Reference-Cited by-同舟云学术

Pharmacokinetics and Safety of Remdesivir in Pregnant and Nonpregnant Women With COVID-19: Results From IMPAACT 2032

Published:2024-06-05 Issue: Volume: Page:
ISSN:0022-1899
Container-title:The Journal of Infectious Diseases
language:en
Short-container-title:

Author:

Brooks Kristina M¹^ORCID,Baltrusaitis Kristin²^ORCID,Clarke Diana F³,Nachman Sharon⁴^ORCID,Jao Jennifer⁵,Purswani Murli U⁶,Agwu Allison⁷,Beneri Christy⁴,Deville Jaime G⁸,Powis Kathleen M⁹¹⁰,Stek Alice M¹¹,Eke Ahizechukwu C¹²¹³,Shapiro David E²,Capparelli Edmund¹⁴¹⁵,Greene Elizabeth¹⁶,George Kathleen¹⁶,Yin Dwight E¹⁷,Jean-Philippe Patrick¹⁷,Chakhtoura Nahida¹⁸,Bone Frederic¹⁹,Bacon Kira¹⁹,Johnston Benjamin¹⁹,Reding Christina¹⁹,Kersey Kathryn²⁰,Humeniuk Rita²⁰,Best Brookie M¹⁴¹⁵,Mirochnick Mark²¹,Momper Jeremiah D¹⁴, ,Lartey Emanuela,Kalra Rohit,Yee Lynn,Stewart James Etta,Cavallo Martha,Baig Mirza,Collinson-Streng Aleisha,Anderson Thuy,Addison Bonnie,Chakraborty Barsha,Avila Cecilia,Caso Giuseppe,Janzen Carla,Carter Michele F,Paul Mary,Eser-Jose Ruth,Pontifes Mariam,Jackson Chivon McMullen,Gomez Nicolette,Alvarez Grace,Mitchell Charles,Potter JoNell,Badell Martina L,Jordan-Thompson Sierra,Floyd Riaun,Thomas-Seaton LaTeshia,Weinberg Adriana,Curran-Hays Shane,Kwon Christine,Glenny Carrie,Aziz Mariam,McNichols Maureen

Affiliation:

1. Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus , Aurora, Colorado , USA

2. Center for Biostatistics in AIDS Research, Harvard T.H. Chan School of Public Health , Boston, Massachusetts , USA

3. Section of Pediatric Infectious Diseases, Boston Medical Center , Boston, Massachusetts , USA

4. Division of Pediatric Infectious Diseases, Stony Brook Children's Hospital , Stony Brook, New York , USA

5. Division of Pediatric Infectious Diseases, Division of Adult Infectious Diseases, Feinberg School of Medicine, Northwestern University , Chicago, Illinois , USA

6. Division of Pediatric Infectious Diseases, BronxCare Health System , Bronx, New York , USA

7. Department of Pediatric Infectious Disease, Johns Hopkins University School of Medicine , Baltimore, Maryland , USA

8. Division of Infectious Diseases, David Geffen School of Medicine, University of California Los Angeles , Los Angeles, California , USA

9. Departments of Medicine and Pediatrics, Massachusetts General Hospital , Boston, Massachusetts , USA

10. Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health , Boston, Massachusetts , USA

11. Division of Maternal Fetal Medicine, Department of Obstetrics and Gynecology, Keck School of Medicine, University of Southern California , Los Angeles, California , USA

12. Division of Maternal Fetal Medicine, Department of Gynecology and Obstetrics, Johns Hopkins University School of Medicine , Baltimore, Maryland , USA

13. Division of Clinical Pharmacology, Johns Hopkins University School of Medicine , Baltimore, Maryland , USA

14. Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego , La Jolla, California , USA

15. Pediatrics Department, School of Medicine-Rady Children's Hospital San Diego, University of California San Diego , San Diego, California , USA

16. IMPAACT Operations Center, FHI 360 , Durham North Carolina , USA

17. Division of AIDS, National Institute of Allergy and Infectious Diseases, National Institutes of Health , Rockville, Maryland , USA

18. National Institute of Child Health and Human Development, National Institutes of Health , Bethesda, Maryland , USA

19. Frontier Science and Technology Research Foundation, Inc , Amherst, New York , USA

20. Gilead Sciences, Inc , Foster City, California , USA

21. Division of Neonatalogy, Chobanian and Avedisian School of Medicine, Boston University , Boston, Massachusetts , USA

Abstract

Abstract Background Pregnant people with coronavirus disease 2019 (COVID-19) experience higher risk for severe disease and adverse pregnancy outcomes, but no pharmacokinetic (PK) data exist to support dosing of COVID-19 therapeutics during pregnancy. We report PK and safety data for intravenous remdesivir in pregnancy. Methods IMPAACT 2032 was a phase 4 prospective, open-label, nonrandomized opportunistic study of hospitalized pregnant and nonpregnant women receiving intravenous remdesivir as part of clinical care. Intensive PK sampling was performed on infusion days 3, 4, or 5 with collection of plasma and peripheral blood mononuclear cells (PBMCs). Safety data were recorded from first infusion through 4 weeks after last infusion and at delivery. Geometric mean ratios (GMR) (90% confidence intervals [CI]) of PK parameters between pregnant and nonpregnant women were calculated. Results Fifty-three participants initiated remdesivir (25 pregnant; median gestational age, 27.6 weeks; interquartile range, 24.9–31.0 weeks). Plasma exposures of remdesivir, its 2 major metabolites (GS-704277 and GS-441524), and the free remdesivir fraction were similar between pregnant and nonpregnant participants. Concentrations of the active triphosphate (GS-443902) in PBMCs increased 2.04-fold (90% CI, 1.35–3.03) with each additional infusion in nonpregnant versus pregnant participants. Three adverse events in nonpregnant participants were related to treatment (1 grade 3; 2 grade 2 resulting in treatment discontinuation). There were no treatment-related adverse pregnancy outcomes or congenital anomalies detected. Conclusions Plasma remdesivir PK parameters were comparable between pregnant and nonpregnant women, and no safety concerns were identified based on our limited data. These findings suggest no dose adjustments are indicated for intravenous remdesivir during pregnancy. Clinical Trials Registration NCT04582266.

Funder

National Institute of Allergy and Infectious Diseases

Eunice Kennedy Shriver National Institute of Child Health and Human Development

National Institute of Mental Health

NIH

Gilead Sciences

Publisher

Oxford University Press (OUP)

Link

https://academic.oup.com/jid/advance-article-pdf/doi/10.1093/infdis/jiae298/58378797/jiae298.pdf

Reference39 articles.

1. Adverse maternal, fetal, and newborn outcomes among pregnant women with SARS-CoV-2 infection: an individual participant data meta-analysis;Smith;BMJ Glob Health,2023

2. Clinical manifestations, risk factors, and maternal and perinatal outcomes of coronavirus disease 2019 in pregnancy: living systematic review and meta-analysis;Allotey;BMJ,2020

3. Severe maternal morbidity and mortality of pregnant patients with COVID-19 infection during the early pandemic period in the US;Matsuo;JAMA Netw Open,2023

4. Effectiveness of the BNT162b2 mRNA COVID-19 vaccine in pregnancy;Dagan;Nat Med,2021

5. Timing and severity of COVID-19 during pregnancy and risk of preterm birth in the International Registry of Coronavirus Exposure in Pregnancy;Smith;BMC Pregnancy Childbirth,2022